Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of ligand-activated transcription factors. Three subtypes of PPARs have been cloned from the mouse and human: i.e., PPARα, PPARγ, and PPARδ. The PPARs are important regulators of carbohydrate and lipid metabolism, cell growth and differentiation, phenotype transition, apoptosis, neovascularization, immunoregulation and the inflammatory response. Compounds that activate PPARs are useful for the treatment and prevention of a variety of clinical disorders including but not limited to the metabolic syndrome, obesity, pre-diabetes, type 2 diabetes, and other insulin resistant syndromes, hypertension, atherosclerosis, dyslipidemia, inflammatory skin diseases such as psoriasis, inflammatory bowel disease, and inflammatory neurodegenerative diseases such as multiple sclerosis and Alzheimer's disease. The metabolic syndrome as referred to herein includes the metabolic syndrome as defined by either the World Health Organization (WHO) or the National Cholesterol Education Program (NCEP) (Zimmet P, et al. Global and societal implications of the diabetes epidemic. Nature. (2001) 414:782-7; Alberti K G, Zimmet P Z. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med. (1998) 15:539-53; Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA (2001) 285:2486-97.).
Examples of known compounds that can activate PPARs include thiazolidinediones (e.g. rosiglitazone, pioglitazone, MK 767 (KRP-297), MCC-555, netoglitazone, balaglitazone, rivoglitazone) that primarily activate PPARgamma or PPARgamma and PPARalpha, and non-thiazolidinediones that can activate any combination of PPARgamma, PPARalpha and PPARdelta (e,g, JTT-501, LSN862, DRF 4832, LM 4156, LY 510929, LY 519818, TY 51501, X 334), certain tyrosine-based derivatives (e.g. GW1929, GW7845), phenylacetic acid-based derivatives, phenoxazine phenyl propanoic acid derivatives (e.g. DRF 2725, DRF 2189), cinammic and dihydrocinammic acid-based derivatives (e.g. tesaglitazar (AZ 242)), and 3-Phenyl-7-propylbenzisoxazoles (Adams A D, et al. Bioorg Med Chem Lett. (2003) 13:931-5), that can activate PPARgamma in combination with PPARalpha or PPARdelta or both PPARalpha and PPARdelta. Although compounds are available that may primarily activate PPARalpha alone or PPARdelta alone, it is common for such compounds to also cause at least some degree of PPARgamma activation as well.
Although drugs that activate PPARgamma have proven to be valuable for the prevention and treatment of type 2 diabetes and a variety of other disorders, the currently available agents cause adverse effects or aggravate certain conditions that can limit the clinical utility and safety of these ligands. Some of the principle limiting side effects or conditions that can be provoked or aggravated by both thiazolidinedione and non-thiazolidinedione compounds that activate PPARgamma either alone or in combination with other PPARs are fluid retention, peripheral edema, pulmonary edema, and congestive heart failure. Both rosiglitazone and pioglitazone have received regulatory approval for the treatment of type 2 diabetes in many countries including the United States and throughout the European Community. The extensive accumulated experience with worldwide use of these drugs has revealed that thiazolidinediones can cause fluid retention, which exacerbates or leads to edema and/or congestive heart failure (CHF). Patients with ongoing edema are prone to adverse effects when on thiazolidinedione therapy, and especially if this is combined with administration with insulin, consisting of up to 16% of patients in the latter group. This is potentially a serious problem, considering that among patients with type 2 diabetes likely to be treated with thiazolidinediones or other non-thiazolidinedione agonist, a significant percentage have CHF or are at high risk for developing CHF because of their high cardiovascular risk profiles. Fluid retention caused by PPAR activators can not only cause volume expansion and peripheral edema, but also can also induce or aggravate life-threatening conditions such as CHF and pulmonary edema. Therefore, there is considerable interest in identifying and using PPARgamma activators that do not cause substantial fluid retention and therefore do not increase the risk for edema and congestive heart failure.
The current invention relates to the surprising discovery that certain ARBs can increase the activity of PPARgamma and can be used to treat or prevent type 2 diabetes, the metabolic syndrome, and other disorders responsive to PPAR activators or PPAR activation, without increasing the risk for fluid retention, peripheral edema, pulmonary edema, or congestive heart failure. Although previous studies have shown that the risk for type 2 diabetes in patients given ARBs is lower than that in patients given other antihypertensive drugs, it could not have been predicted that certain ARBs could be used to prevent or treat type 2 diabetes, the metabolic syndrome or other disorders responsive to PPAR ligands.
It has been unclear whether ARBs actually decreased the risk for diabetes or whether the drugs to which they were being compared increased the risk for diabetes. For example, the lower risk of diabetes reported in patients given ARBs versus beta blockers or thiazide diuretics was due to the fact that beta blockers and thiazide diuretics aggravate insulin resistance and therefore, the results of clinical studies comparing ARBs to other agents cannot be used to predict whether ARBs can be used to prevent or treat diabetes or other disorders responsive to PPARgamma activators.
Several trials have investigated the effects of ARBs on glucose homeostasis but the results are conflicting and controversial (for a review of this subject, see: Bernobich E, et al. Drugs (2002) 62:1295-1314). There are no data available that consistently demonstrate that ARBs improve insulin sensitivity, attenuate insulin resistance, or can be used to treat or prevent type 2 diabetes, the metabolic syndrome, or other insulin resistance syndromes. Expert opinions expressed in the medical and scientific literature hold that drugs that block angiotensin II type 1 receptors (ARBs) (also known as “sartans”) are “metabolically neutral” (Epstein M. Angiotensin II Receptor Antagonists: Current Status. In: Angiotensin II Receptor Antagonists. Epstein M and Brunner H R (eds), Hanley & Belfus, Inc., Philadelphia, (2002) pp 257-261). For example, the ARB losartan has a neutral effect on glucose metabolism, insulin sensitivity, and serum concentrations in patients with mild hypertension (Bernobich E, et al. Drugs (2002) 62:1295-1314), and in clinical studies with diabetic patients, candesartan does not appreciably alter their hemoglobin A1c, glucose concentration or lipid profile (Easthope S E, et al. Drugs 2002;62:1253-87).
In a recent clinical trial (LIFE trial) where the ARB losartan was compared to the β-blocker atenolol, the incidence of new-onset type 2 diabetes was greater in the atenolol treated patients than in those treated with losartan (Dahlof B, et al. Lancet (2002) 359:995-1003). However, β-blockers like atenolol are known to be clinically diabetogenic and can promote or worsen insulin resistance and thereby promote the development of type 2 diabetes (Teuscher A U, et al. J Hypertens Suppl. (1997) 15:S67-75). Therefore, the lower incidence of new-onset type 2 diabetes in the losartan arm of the study actually reflected an increase in the incidence of new-onset type 2 diabetes in the atenolol arm. Studies showing a lower incidence of new onset diabetes in patients treated with the ARB candesartan compared to patients treated with thiazide diuretics also indicate that the ARB candesartan did not decrease the risk for diabetes, rather, the thiazide diuretic increased the risk for diabetes. Consequently, the prior art could not be used to predict that losartan, telmisartan, irbesartan, or any other ARB could be used to prevent or treat type 2 diabetes, the metabolic syndrome, or other forms of insulin resistance. Moreover, because the ARBs have important structural chemical differences, any unusual or unexpected results obtained with one ARB cannot be used to predict that similar results would be obtained with another ARB.
In the obese Zucker rat, Henriksen et al. found that oral administration of an extremely high dose of irbesartan improved insulin sensitivity but apparently failed to improve lipid levels (Henriksen E J, et al. Selective angiotensin II receptor antagonism reduces insulin resistance in obese Zucker rats. Hypertension. (2001) 38:884-90). However, the obese Zucker rat is an unusual form of obesity and insulin resistance that is caused by mutations in the leptin receptor and furthermore, the rats studied by Henriksen did not have type 2 diabetes. Mutations in leptin receptors in humans are extremely rare and almost never account for type 2 diabetes, obesity, insulin resistance, or the metabolic syndrome in humans. Therefore, the studies by Henriksen et al. in which an extremely high dose of irbesartan was found to improve insulin sensitivity in obese Zucker rats can not be used to predict or imply that irbesartan or any other ARB could be used to activate PPARγ in vivo or be used to treat or prevent type 2 diabetes, the metabolic syndrome, or other insulin resistance syndromes in humans.
In 2002, after the current discovery was made, Sharma and colleagues reported that very high concentrations of angiotensin II can inhibit differentiation of human preadipocytes and that high concentrations of irbesartan can enhance adipogenesis (Janke J, et al. Mature adipocytes inhibit in vitro differentiation of human preadipocytes via angiotensin type 1 receptors. Diabetes. (2002) 51:1699-707). Based on these findings and recent evidence showing that lack of adipose tissue can promote diabetes by causing excess storage of fat in muscle, liver, and pancreas (Danforth E, Jr. Failure of adipocyte differentiation causes type II diabetes mellitus? Nat Genet. (2000) 26:13), Sharma and colleagues proposed that blockade of the renin-angiotensin system per se might prevent diabetes by promoting the recruitment and differentiation of adipocytes (Sharma A M, et al. Angiotensin blockade prevents type 2 diabetes by formation of fat cells. Hypertension. (2002) 40:609-11). In the current studies, we have found that moderate concentrations of telmisartan and higher concentrations of irbesartan can activate PPARγ which is known to promote adipogenesis, however, other ARBs failed to show any effects on PPARγ gamma activity or adipogenesis. Thus, blockade of angiotensin receptors per se is not sufficient to promote increased PPARgamma activity or adipogenesis and not sufficient to prevent or treat type 2 diabetes or any other insulin resistance syndrome including the metabolic syndrome.
In light of a number of clinical and experimental studies suggesting that angiotensin converting enzyme (ACE) inhibitors can improve insulin sensitivity and decrease the incidence of new onset type 2 diabetes in patients with hypertension, the question again arises as to whether pharmacological interruption of the renin-angiotensin system by other means, such as with angiotensin receptor blockers (ARBs), could also be predicted to be useful for preventing or treating type 2 diabetes or other insulin resistance syndromes (Yusuf S, et al. Ramipril and the development of diabetes. JAMA. 2001;286:1882-5; Hansson L, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomized trial. Lancet. (1999) 353:611-6; Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. (2002) 288:2981-97; Bernobich E, et al. The role of the angiotensin system in cardiac glucose homeostasis: therapeutic implications. Drugs. (2002) 62:1295-314). However, recent studies have shown that the insulin sensitizing effects of ACE inhibitors are related to their effects on kinin metabolism rather than their effects on the renin-angiotensin system (Tomiyama H, et al. Kinins contribute to the improvement of insulin sensitivity during treatment with angiotensin converting enzyme inhibitor. Hypertension. (1994) 23:450-5; Shiuchi T, et al. ACE inhibitor improves insulin resistance in diabetic mouse via bradykinin and NO. Hypertension. (2002) 40:329-34; Bernobich E, et al. The role of the angiotensin system in cardiac glucose homeostasis: therapeutic implications. Drugs. (2002) 62:1295-314). Thus, based on the results of studies using ACE inhibitors, it could not have been predicted that any of the existing ARBs would activate PPARγ and be useful for preventing or treating type 2 diabetes, the metabolic syndrome or any other insulin resistance syndrome.